Prostaglandin D2 (PGD2) is the inflammatory mediator produced and released in the largest amount by mast cells activated by crosslinking of an allergen with the immunoglobulin E on the cells (Non-patent Literature (NPL) 1), and is considered to play an important role in causing allergic symptoms. PGD2 is detected at a high concentration in an asthmatic's bronchoalveolar lavage fluid (Non-patent Literature (NPL) 2), and it was reported that bronchoconstriction induced by PGD2 inhalation was more clearly observed in asthmatic patients than in healthy subjects (Non-patent Literature (NPL) 3).
On the other hand, synthases that generate PGD2 are referred to as prostaglandin D synthases, which has been classified into two distinct types: hematopoietic prostaglandin D synthase and lipocalin-type prostaglandin D synthase. PGD2 participates in the onset and exacerbation of various diseases, including allergies, and in the regulatory mechanisms of the body. Therefore, pharmaceutical preparations that can improve abnormal production of PGD2 are considered to be very effective for the treatment of various diseases.
Human hematopoietic prostaglandin D synthases (H-PGDS) are mainly distributed throughout the placenta, lung, fetus liver, lymph node, brain, heart, thymus, bone marrow, and spleen. Moreover, at the cellular level, they are reported to be expressed in microglial cells in the brain; megakaryocytes; many like antigen-presenting cells such as Langerhans cells in the skin, Kupffer cells in the liver, macrophages, and dendritic cells; mast cells; and Th2 cells.
Moreover, from the fact that H-PGDS are highly expressed in mast cells or inflammatory cells in the nasal mucosa of allergic rhinitis patients, or in nasal polyps of chronic sinusitis patients, it is thought that PGD2 generated by H-PGDS plays an important role in the onset and exacerbation of allergic diseases, such as asthma, rhinosinusitis, dermatitis, and chronic obstructive pulmonary disease (Non-patent Literature (NPL) 4). Further, the expression of H-PGDS is observed in the necrosed part of skeletal muscle, in which the expression of H-PGDS is generally detected (Non-patent Literature (NPL) 5). For this reason, it is suggested that PGD2 generated by H-PGDS participates in diseases accompanied by tissue damage, such as muscular dystrophy, amyotrophic lateral sclerosis, multiple sclerosis, inflammatory colitis, rheumatoid arthritis, and chronic obstructive arterial disease.
Therefore, an H-PGDS inhibitor is expected to find application as a pharmaceutical preparation that is useful as an agent for preventing and/or treating diseases, such as allergic disease and inflammatory disease in which PGD2 generated by H-PGDS or the metabolite participates, muscle necrosis, and traumatic brain injury.
There are some reports on an H-PGDS inhibitor (for example, Patent Literature (PTL) 1 and 2). Patent Literature (PTL) 3 discloses an H-PGDS inhibitor having a structure similar to that of the compound of the present invention. In addition, piperidine compounds have been widely studied as useful pharmacological agents in addition to H-PGDS inhibitors.
Patent Literature (PTL) 4 discloses, as a hedgehog signaling inhibitor, a piperazine compound having a furylcarbonyl piperazine structure.
Patent Literature (PTL) 5 discloses a wide range of piperazine compounds as compounds that interact with potassium channels.